Triazolo[1,5-c]pyrimido[1,4]azines as bronchodilators

ABSTRACT

Substituted 1,2,4-triazolo[1,5-c]pyrimido[1,4]-azines have been found to have potent bronchodilator activity. Also, pharmacological methods for inducing bronchodilation using such compounds, pharmaceutical compositions containing such compounds, and synthetic intermediates, including 1,2,4-triazolo[4,3-c]-pyrimido[1,4]azines, for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending USSN 152,443,which was filed on Feb. 5, 1988, now abandoned.

TECHNICAL FIELD

This invention relates to novel heterocyclic compounds exhibitingbronchodilator activity. Pharmacological methods of using suchcompounds, pharmaceutical formulations containing such compounds andsynthetic intermediates for preparing such compounds are also described.

BACKGROUND OF THE INVENTION

A variety of aromatic heterocyclic compounds are known to exhibitbronchodilator activity. One of the most widely used compounds fortreatment of mammals is theophylline, which has the structure shownbelow: ##STR1##

Numerous attempts to obtain a safer, more potent bronchodilator have notyet supplanted theophylline.

Pyrimido[5,4-]oxazines are known compounds which are reported bySazonov, et al., Khimiya Geterotsiklicheskikh Soedinenii, 1973, 171;ibid., 1972, 1285, and ibid., 1976, 681. These compounds, which have notbeen described as bronchodilators, have the following structure:##STR2## wherein R is amino, acetamido, hydrogen or methyl; R' ishydrogen, methyl, hydrazino, piperidino, morpholino, methoxy,methylthio, mercapto, chloro or hydroxy; and R" is hydrogen, methyl,ethyl, propyl, or dimethyl.

Pyrimido[4,5-b][1,4]oxazines are known compounds which are reported byMelik-Ogandzhanyan, et al., Khimiya Geterotsiklicheskikh Soedinenii,1985, 974. The corresponding 4-chloro, 4-hydroxy, 4-dialkylamino,4-morpholino and 4-piperidino derivatives are reported. They have thefollowing structure: ##STR3## wherein R is methyl or hydrogen and R, ischloro, hydroxy, N,N-dimethylamino, N,N-diethylamino, morpholino orpiperidino. None of the reported compounds were described asbronchodilators.

Some pyrimido[5,4-b][1,4]thiazines are known, reported by E. F.Schroeder and R. M. Dodson, J. Amer. Chem. Soc., 84, 1904-1913 (1962)and by R. N. Henri, R. A. Lazarus and S. J. Benkovic, J. Med. Chem., 26,559-563 (1983). None of the reported compounds were described asbronchodilators.

U.S. Pat. Nos. 4,477,450 and 4,572,910, respectively, disclosetriazolo[4,3-c]pyrimidines and triazolo[1,5-c]pyrimidines which containa heterocyclic amine moiety such as piperazino, piperidino, morpholinoor thiomorpholino on the 5- and/or 7-position of the pyrimidine ring.These compounds are bronchodilators.

Triazolo[1,5-c]pyrimido[4,5-b][1,4]oxazines,triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazines andtriazolo[1,5-c]pyrimido[5,4-b][1,4]thiazines have not previously beenreported.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted1,2,4-triazolo[1,5-c]pyrimido[1,4]azines which are bronchodilators. Theinvention also relates to a method for obtaining bronchodilation in amammal using a 1,2,4-triazolo[1,5-c]pyrimido[1,4]azine of the invention,and to pharmaceutical compositions comprising an effective amount of a1,2,4-triazolo[1,5-c]pyrimido[1,4]azine of the invention and apharmaceutically acceptable carrier. The invention also relates tosynthetic intermediates useful for preparing pharmaceutical compounds ofthe invention.

More specifically, the present invention relates to compounds of FormulaI below ##STR4## wherein A is methylene or carbonyl; B is methylene,carbonyl or -CHR₉ -; Q is N-R₇ or O, with the proviso that when Q is Othen A is methylene and B is methylene or carbonyl; Y is N-R₁₀, O, S, SOor SO₂, with the provisos that when Y is N-R :, Q is 0, when Q is N-R₇,Y is not N-R₁₀ and B is not carbonyl, and when Q is 0, Y is N-R₁₀ ; R₂is hydrogen or lower alkyl; R₅ is lower alkyl; R₇ is hydrogen, loweralkyl, benzyl or acetyl, with the proviso that when R₇ is hydrogen oracetyl and Y is S, SO or SO₂, then A is methylene; R₉ is lower alkyl;and R₁₀ is lower alkyl or benzyl; and pharmaceutically acceptable acidaddition salts of compounds wherein A is methylene and B is methylene or--CHR₉ --. Three subsets of Formula I are described herein below:compounds of Formula VI wherein Y is O and Q is NR₇, compounds ofFormula VI wherein Y is N-R₁₀ and Q is O and compounds of Formula XIXand Formula XXVI wherein Y is shown as S, but could also be oxidized toSO or SO₂.

The instant invention also provides novel compounds of Formula II below##STR5## wherein A is methylene or carbonyl; B is methylene, carbonyl or-CHR₉ --; Q is N-R₇ or O with the proviso that when Q is O then A ismethylene and B is methylene or carbonyl; Y is N-R₁₀, O, S, SO or SO₂,with the provisos that when Y is N-R₁₀, Q is O when Q is N-R₇, Y is notN-R₁₀ and B is not carbonyl, and when Q is O, Y is N-R₁₀ ; R₅ is loweralkyl; R₇ is hydrogen, lower alkyl or benzyl, with the proviso that whenR₇ is hydrogen and Y is S, SO or SO₂, then A is methylene; R₉ is loweralkyl; and R₁₀ is lower alkyl or benzyl. The compounds of Formula II areuseful intermediates for preparing compounds of Formula I.

Also, the instant invention further provides compounds of Formula IIIbelow ##STR6## wherein A is methylene or carbonyl; B is methylene,carbonyl or --CHR₁₉ ; Q is N-R₇ or O, with the proviso that when Q is O,then A is methylene and B is methylene or carbonyl; Y is N-R₁₀,O, S, SOor SO₂ with the provisos that when Y is N-R ₁₀, Q is O, when Q is N-R₇,Y is not N-R₁₀ and B is not carbonyl, and when Q is O, Y is N-R₁₀ ; R₂is hydrogen or lower alkyl; R₅ is lower alkyl; R₇ is hydrogen, loweralkyl, benzyl or acetyl, with the proviso that when R₇ is hydrogen oracetyl and Y is S, SO or SO₂, then A is methylene; R₉ is lower alkyl;and R₁₀ is lower alkyl or benzyl. The compounds of Formula III are alsouseful intermediates for preparing compounds of Formula I.

"Lower alkyl" as used in the instant specification and claims designatesstraight and branched-chain alkyl groups containing one to about 4carbon atoms. Preferred lower alkyl groups are methyl and ethyl.

The presently preferred compounds of the invention are listed below.These compounds are preferred because of their generally higher potencyin protecting against histamine-induced contraction of isolated guineapig tracheal tissue. This assay is discussed in greater detail below.

Specific examples of preferred compounds which are active in theaforementioned assay at concentrations of 5 micrograms per milliliter orlower are:

8,9-dihydro-2-ethyl-5-methyl-7H-1,2,4-triazolo[1,5-c]-pyrimido[5,4-b]1,4]oxazin-8-one,

8,9-dihydro-2,5,7-triethyl-1,2,4-triazolo[1,5-c]pyrimido-[5,4][1,4]oxazin-8-onehydrate,

2,5-diethyl-8,9-dihydro-7-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one,

7-(n-butyl)-2,5-diethyl-8,9-dihydro-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one

57-benzyl-8,9-dihydro-2,5,9-triethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one,

8,9-dihydro-5-ethyl-2-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,

7-benzyl-8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,5,7-diethyl-8,9-dihydro-2-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,-benzyl-2,5-diethyl-8,9-dihydro-1,2,4-triazolo[1,5-c]pyrimido[

5,4-b][1,4]thiazine,

8,9-dihydro-2-ethyl-5-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazine,

2,5-diethyl-8,9-dihydro-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin-8-one,

2,9-diethyl-8,9-dihydro-7H-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin-8-one,

8,9-dihydro-5,9-dimethyl-2-ethyl-7H-1,2,4-triazolo[1,5-c]

]oxazin-8-one,

8,9-dihydro-2,5,9-trimethyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin-8-one,

8,9-dihydro-2,5,9-triethyl-7H-1,2,4-triazolo[1,5-c]pyrimido[

5,4-b][1,4]oxazin-8-one, C,5,9-diethyl-8,9-dihydro-2-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin-8-one,

2,5-diethyl-8,9-dihydro-9-methyl-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin-8-one,(n-butyl)-8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolo[

1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one,

2,7-diethyl-8,9-dihydro-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,

2,5-diethyl-8,9-dihydro-7H-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,

2,5-diethyl-8,9-dihydro-7-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,

2,5-diethyl-8,9-dihydro-10-methyl-1,2,4-triazolo[1,5-c]pyrimido[4,5-b][1,4]oxazine,and

8,9-dihydro-2,5,10-triethyl-1,2,4-triazolo[1,5-c]pyrimido[4,5-b][1,4]oxazine.

Particularly preferred compounds of Formula I are the last fourteenmentioned above.

Compounds of Formula I are bronchodilators. The bronchodilator activityof the compounds of Formula I may be shown by the measurement of effectson isolated tracheal spirals. This is a well-known and long establishedin vitro test method. The bronchodilator activity is determinedaccording to the following procedure: Female guinea pigs were sacrificedand each trachea removed and cut into a spiral strip. This strip wasmounted in a constant temperature (37° C.) muscle bath having a volumeof approximately 15 ml. The bathing medium was Krebs-Henseleit solution.Movement of the tracheal strip was measured by means of an isometrictransducer connected to an electric recorder. The bath was aerated witha mixture of 95% carbon dioxide and 5% oxygen. Contractions were inducedin the strips by the addition of a suitable amount of histamine,leukotriene C₄, acetylcholine or barium chloride. The amount of a givencompound of Formula I (measured in mcg/ml) required to provide greaterthan 75% relaxation of drug-induced contraction is considered aneffective concentration. For comparison, a well known standardbronchodilator, aminophylline (the ethylenediamine salt oftheophylline), requires concentrations of 50 mcg/ml versus histamine,100 mcg/ml versus acetylcholine and 10 mcg/ml versus barium chloride toprovide greater than 75% relaxation.

The compounds of Formula I which were most active in the above describedin vitro test, including most of those listed above as preferredcompounds, were tested in vivo in the guinea pig for bronchodilatoractivity using the so-called Konzett-Rossler in vivo test method. Theactivity was determined according to the procedure which follows. TheKonzett-Rossler technique [H. Konzett and R. Rossler,Naunyn-Schmiedebergs Arch. Pharmakol., 195, 71-74 (1940)]was used toassess the effect of test drugs on antigen challenge of male Hartleystrain guinea pigs (350-500 g). Sensitized (50 mg/kg ovalbumin, i.p.,14-21 days previously) or naive animals were anesthetized withpentobarbital (70 mg/kg, i.p.) and spontaneous respiration eliminatedwith succinylcholine (2 mg/kg i.p.). The trachea was cannulated andrespiration maintained under positive pressure with a miniatureventilator (5 ml/breath, 87/minute, 10 cm water). Bronchoconstrictorresponses were represented as increased excursions of the tracing on aphysiological recorder of air overflow to the lungs measured by apneumotachograph in series with a differential pressure transducer.Sensitized animals were challenged with ovalbumin (100 mcg/kg, i.v.)after the i.p. or p.o. administration of test drugs. Active compoundsare those which demonstrate an intraperitoneal or oral IC₅₀ of 10 mg per25 mg per kg or less, and preferably an IC₅₀ of 10 mg per kg or less.Most preferred compounds are active at 10 mg per kg.

The compounds of Formula I may be administered to mammals in order toobtain bronchodilation. The compounds may be administered orally,parenterally or by inhalation. Preferably they are administered orallyin tablets or capsules. The usual effective human dose will be in therange of 0.1 to 50 mg/kg of body weight.

Salts of compounds of Formula I wherein A is methylene and B ismethylene or --CHR₉ -- are generally prepared by reaction with anequimolar amount of a relatively strong acid, preferably an inorganicacid such as hydrochloric, sulfuric or phosphoric acid, in a polarsolvent. Isolation of the salt is facilitated by the addition of asolvent in which the salt is insoluble, an example of such a solventbeing diethyl ether.

The compounds of Formula I, either as the free base or in the form of apharmaceutically acceptable acid addition salt, can be combined withconventional pharmaceutical diluents and carriers to form such dosageforms as tablets, capsules, suspensions, solutions, suppositories andthe like.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Examples of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid,and the like. Liquid carriers include syrup, peanut oil, olive oil,water and the like. Similarly, the carrier or diluent can include a timedelay material well known to the art, such as glyceryl monostearate orglyceryl distearate, these being employed alone or, for example, incombination with a wax.

When Y is N-R₁ or O, the compounds of Formula VI, which are subsets ofcompounds of Formula I, may be prepared according to Reaction Scheme Ibelow, wherein the various substituents are as defined in the context ofFormula I above with the exception that R₇ may only be hydrogen, alkylor benzyl. ##STR7##

In step (1), a 4-hydrazinopyrimido[5,4-b][1,4]-oxazine, or-[4,5-b][1,4]oxazine or -oxazinone of Formula IV, which can be preparedas described in Reaction Scheme II below, is reacted with an orthoesterof the formula R₂ C(OAlk)₃ to provide a novel compound of Formula V.Orthoesters of the formula R₂ C(OAlk)₃ are well known and readilyavailable. Examples of suitable orthoesters include trimethylorthoformate, triethyl orthoformate, triethyl orthoacetate, triethylorthopropionate and the like. Since the orthoesters are liquids, it isconvenient to mix the compound of Formula IV with an excess oforthoester and to heat the mixture at reflux until reaction is complete.

In step (2), the compound of Formula V is heated with a suitable reagentto provide a product of Formula VI, a subset of the compounds of FormulaI. This reaction is preferably carried out by heating the reactionmixture at its reflux temperature in a solvent inert to these conditionssuch as a lower alkanol. In general, the preferred reagents to effectthe reaction of step (2) are alkali metal alkoxides such as sodiummethoxide or sodium ethoxide, in catalytic amounts. It is also possibleto use aqueous lower alkanoic acids such as formic acid, acetic acid andpropionic acid to effect the reaction of step (2). The products ofFormula VI, a subset of the compounds of Formula I, are isolated byconventional methods such as filtration, extraction or chromatography.

Compounds of either Formula V or VI, wherein R₇ is hydrogen, may bereadily acetylated by conventional methods.

Compounds of Formula IV, appearing in Reaction Scheme I above, may beprepared according to Reaction Scheme II below wherein the varioussubstituents are as defined in the context of Formula I above when Y isO or N-R₁₀ with the exception that R₇ may only be hydrogen, alkyl orbenzyl. In this scheme, Q₁ and Q₂ are either N-H and O or O and N-H,respectively. In structures of the scheme of Formula VII or VIII eitherA or B, but not both simultaneously, must be carbonyl, while instructures IX and X, A and B can only be methylene or --CHR₉ --.##STR8##

The compounds of Formula VII wherein Q₁ is NH, Q₂ is O, A is carbonyland B is methylene or --CHR₉ -- are known and can be synthesized usingthe general procedure described by Sazonov, et al., KhimiyaGeterotsiklicheskikh Soedinenii, 1973, 171; ibid., 1972, 1285, andibid., 1976, 681, each of these three publications being incorporatedherein by reference. Variations of the procedure described in thesepublications are conventional and involve primarily variations either inthe starting amidine or in the added 2-haloalkanoic ester or acid.

The compounds of Formula VII wherein Q₁ is O, Q₂ is NH, A is methylene,and B is carbonyl, are also known, and can be synthesized using thegeneral procedures described by Melik-Ogandzhanyan, et al., KhimiyaGeterotsiklicheskikh Soedinenii, 1985, 974, incorporated herein byreference. Variations of the procedures described in this publicationare conventional and involve primarily variations in the startingamidine

In step (3) of Reaction Scheme Il, a compound of Formula VII is reactedwith a benzyl halide or an alkyl halide such as an alkyl iodide or alkylbromide to provide a compound of Formula VIII. The reaction is conductedin a lower alkanol solvent in the presence of an alkali metal alkoxidesuch as sodium methoxide or in the solvent N,N-dimethylformamide in thepresence of sodium hydride. The reaction mixture is generally heated ator near its reflux temperature in an alkanol solvent or from 20 to 50°C. in N,N-dimethylformamide.

When Q₁ is Q₂ is N-H the reaction preferably uses sodium hydride inN,N-dimethylformamide rather than an alkali metal alkoxide in analkanol.

Step (4) involves the reaction of a compound of Formula VIII withhydrazine hydrate optionally in a lower alkanol solvent such as n-butylalcohol to provide a novel intermediate of Formula IV.

The compounds of Formula IV wherein A is methylene and B is methylene or--CHR₉ -- can be made by sequential application of steps (5) and (6). Instep (5), the amide compounds of Formula VIII are reduced to the aminesof Formula X by reaction with a borane reagent. Generally, 4 moles ofborane per mole of the compound of Formula VIII are employed, and thereaction is accompanied by heating at a temperature up to the refluxtemperature of the mixture. The reaction is carried out in an inertsolvent such as tetrahydrofuran and the borane reagent employed may be,for example, a methyl sulfide complex of borane in tetrahydrofuran.

In step (6), the amines of Formula X are reacted with hydrazine hydratein the same fashion as in step (4) to provide the compounds of FormulaIV.

The compounds of Formula X can also be provided by sequentialapplication of steps (7) and (8). Thus in step (7), the amide VII isfirst reduced with a borane reagent, in a fashion similar to that ofstep (5), to obtain the compound of Formula IX. Alkylation of compoundIX in step (8) then provides a compound of Formula X.

Compounds of Formula IV wherein R₇ is hydrogen are obtained by omittingthe alkylation steps (3) or (8), and instead reacting either a compoundof Formula VII or a compound of Formula IX with hydrazine hydrate, usingthe method of step (4).

When Y is S and A is carbonyl and B is methylene or --CHR₉ --, thecompounds of Formula XIX, which are a subset of compounds of Formula I,can be prepared according to Reaction Scheme III below, wherein thevarious substituents are as defined in the context of Formula I abovewith the exception that R₇ may only be alkyl or benzyl. ##STR9##

Compounds of structure XI, where R₇ is lower alkyl or benzyl, are knownand can be prepared as described by Gewald in J. Prakt. Chem., 32, 26-30(1966), the disclosure of which is incorporated herein by reference.Compounds of Formula XIII are prepared in step (9) using Gewald'sgeneral procedure, but using an orthester of the formula R₅ C(OAlk)₃rather than triethyl orthoformate.

An alternate route to the preparation of the compounds of Formula XIIIcan be employed and is shown in step (9'). It involves the syntheticprocess described by Gewald with the exception that the compound ofFormula XII is reacted with acetamidine hydrochloride in a refluxingsolvent, preferably a lower chain alcohol, containing 1.5 to 2.0equivalents of sodium methoxide, to form the compounds of Formula XIII.

The reaction of step (10) to form the compounds of Formula XIV can becarried out according to the procedure of Gewald, J. Prakt. Chem., 32,26-30 (1966), although only 5-mercapto-6-phenylamino-3H-pyrimidin-4-onewas specifically described by him.

Step (11) to form the novel compounds of Formula XV is carried out byreacting a compound of Formula XIV with a 2-haloalkanoic acid inrefluxing sodium hydroxide solution, followed by refluxing the resultantisolated intermediate in acetic anhydride to provide the compounds ofFormula XV.

Step (12) involves reaction of the compounds of Formula XV withphosphorus oxychloride to provide the 4-chloro compounds of Formula XVI.

Step (13) involves reaction of hydrazine or hydrazine hydrate with thecompounds of Formula XVI to provide the novel compounds of Formula XVII.

Step (14) involves reaction of a hydrazino compound of Formula XVII withan orthoester of the formula R₂ C(OAlk)₃ to provide a novel compound ofFormula XVIII. Orthoesters of the formula R₂ C(OAlk)₃ are well known andreadily available compounds or may be prepared by known methods.Specific examples of suitable orthoesters include trimethylorthoformate, triethyl orthoformate, triethyl orthoacetate, triethylorthopropionate and the like. Since the orthoesters are liquids, it isconvenient to mix an excess of orthoester with the compound of FormulaXVII and reflux until the desired compound of Formula XVIII is formed.

In step (15) the compound of Formula XVIII is rearranged by refluxing ina solution of a catalytic amount of methanolic sodium methoxide to formthe compounds of Formula XIX, a subset of the compounds of Formula I,wherein A is carbonyl.

Compounds of Formula XIX are solids which may be readily isolated byconventional methods such as filtration, extraction or chromatography.Structural assignments may be confirmed by infrared and nuclear magneticresonance spectral analyses.

When Y is S, A is methylene and B is methylene or --CHR₉ --, thecompounds of Formula XXVI, which are a subset of compounds of Formula I,can be prepared according to Reaction Scheme IV below, wherein thevarious substituents are as defined in the context of Formula I above.##STR10##

The 5,6-dihydro-3-ethoxy-2-ethoxycarbonyl-2H-[1,4]thiazines of FormulaXX can be prepared according to the procedure of Great Britain patentapplication 2,143,234A and Henrie II, Robert N., Lazarus, Robert A., andBenkovic, Stephen J., J. Med. Chem., 26, No. 4, 559-563 (1983), thedisclosures of both of which are incorporated herein by reference. Thecompound of Formula XX is reacted in step (16) with an amidine salt in arefluxing alcohol to which has been added 2.0 to 2.5 equivalents ofsodium methoxide; thus forming the oxopyrimido[5,4-b][1,4]thiazines ofFormula XXI.

Step (17) involves reaction of the compounds of Formula XXI withphosphorus oxychloride to provide the 4-chloro compounds of FormulaXXII.

Step (18) involves reaction of hydrazine or hydrazine hydrate with thecompounds of Formula XXII to provide the novel hydrazino compounds ofFormula XXIII.

Step (19) involves reaction of a hydrazino compound of Formula XXIIIwith an orthoester of the formula R₂ C(OAlk) to provide a novel compoundof Formula XXIV.

Orthoesters of the formula R₂ C(OAlk)₃ are well known and readilyavailable compounds or may be prepared by known methods. Specificexamples of suitable orthoesters include trimethyl orthoformate,triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionateand the like. Since the orthoesters are liquids, it is convenient to mixan excess of orthoester with the compound of Formula XXIII and refluxuntil the desired compound of Formula XXIV is formed.

In step (20) the compound of Formula XXIV is rearranged by refluxing ina solution of a catalytic amount of methanolic sodium methoxide to formthe compounds of Formula XXV.

Step (21) involves the further reaction of the8,9-dihydro-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazines ofFormula XXV with an alkyl, acyl or benzyl halide to form the compoundsof Formula XXVI, which are a subset of compounds of Formula I. Althoughin the specific examples described herein alkylation was carried outusing a compound of Formula XXV, alkylation could have also been carriedout using a compound of either Formula XXII or Formula XXIV.

Compounds of Formula XXII, Formula XXIV, Formula XXV or Formula XXVI canbe oxidized to their respective sulfoxides by reaction with sodiummetaperiodate, or a peracid such as meta-chloroperbenzoic acid.Similarly, any of the compounds previously mentioned which are capableof oxidation to the sulfoxide may be independently oxidized to thesulfone by the action of a peracid such as metachloroperbenzoic acid.Alternatively, any sulfoxide may be further oxidized to form thecorresponding sulfone.

All compounds of Formula XXVI, a subset of compounds of Formula I, aresolids which may be readily isolated by conventional methods such asfiltration, extraction or chromatography. Structural assignments may beconfirmed by infrared and nuclear magnetic resonance spectral analyses.

The following examples are provided to illustrate the methods used inthe invention. They are not intended to limit the invention.

EXAMPLE 1 Step 1

Preparation of8,9-Dihydro-5,7-dimethyl-3-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4,-b]-[1,4]oxazin-8-one

A mixture of 4.0g (0.019 mole) of6,7-dihydro-2,8-dimethyl-4-hydrazinopyrimido[5,4-b][1,4]oxazin-7-one and25 ml of triethyl propionate was heated first at 110° C for about 16hours and then at 130° C for an additional 25.5 hours. The mixture wasevaporated by passing a stream of nitrogen gas over it, and 1.0g of thesolid residue was separated for reaction in Step 2. The remainder of theresidue was dissolved in dichloromethane and passed through a silicaflash chromatography column, eluting sequentialy with ethyl acetate andacetone. The fractions were checked by thin layer chromatography, andwere evaporated to provide solid fractions. A later fraction whichshowed only one component was determined to be8,9-dihydro-5,7-dimethyl-3-ethyl-1,2,4 -triazolo[4,3-c]pyrimido[5,4-b][1,4]-oxazin-8-one, m.p. 200° C. Analysis: Calculated for C₁₁ H₁₃ N₅O₂ : %C, 53.4; %H, 5.3; %N, 28.3: Found: %C, 53.4; %H, 5.3; %N, 28.4.

EXAMPLES 2-22

Using the method of Step 1, Example 1, the indicated intermediates ofFormula IV wherein Y is O, Q is N-R₇ and B is methylene or --CHR₉ - werereacted with the indicated trialkyl orthoesters to provide novelintermediates of Formula V (Table IA).

                                      TABLE IA                                    __________________________________________________________________________                 Intermediate of Formula V                                        Example                                                                            Orthoester                                                                            R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                            B      A                                          __________________________________________________________________________     2   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CH.sub.2                                                                             C═O                                         orthopropionate                                                           3   triethyl                                                                              H    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             C═O                                         orthoformate                                                              4   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             C═O                                         orthopropionate                                                           5   triethyl                                                                              H    CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2                                                                             C═O                                         orthoformate                                                              6   triethyl                                                                              CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             C═O                                         orthoacetate                                                              7   triethyl                                                                              CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2                                                                             C═O                                         orthoacetate                                                              8   triethyl                                                                              CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2                                                                             C═O                                         orthoacetate                                                              9   triethyl                                                                              H    CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2                                                                             C═O                                         orthoformate                                                             10   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H    CH.sub.2                                                                             C═O                                         orthopropionate                                                          11   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CHCH.sub.2 CH.sub. 3                                                                 C═O                                         orthopropionate                                                          12   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CHCH.sub.3                                                                           C═O                                         orthopropionate                                                          13   triethyl                                                                              CH.sub.3                                                                           CH.sub.3                                                                           H    CHCH.sub.3                                                                           C═O                                         orthoacetate                                                             14   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H    CHCH.sub.2 CH.sub.3                                                                  C═O                                         orthopropionate                                                          15   triethyl                                                                              CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  H    CHCH.sub.2 CH.sub.3                                                                  C═O                                         orthoacetate                                                             16   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H    CHCH.sub.3                                                                           C═O                                         orthopropionate                                                          17   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2                                                                             C═O                                         orthopropionate                                                          18   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CH.sub.2                                                                             CH.sub.2                                        orthopropionate                                                          19   triethyl                                                                              H    CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             CH.sub.2                                        orthoformate                                                             20   triethyl                                                                              CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             CH.sub.2                                        orthoacetate                                                             21   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             CH.sub.2                                        orthopropionate                                                          22   triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2                                                                             CH.sub.2                                        orthopropionate                                                          __________________________________________________________________________

EXAMPLES 23-40

Using the method of Step 1, Example 1, the indicated intermediates ofFormula IV wherein Y is N--R₁₀, Q is O, and A is methylene were reactedwith the indicated trialkyl orthoesters to provide novel intermediatesof Formula V (Table IB). Example 39 has not actually been carried out.

                  TABLE IB                                                        ______________________________________                                        Exam-             Intermediate of Formula V                                   ple   Orthoester  R.sub.2  R.sub.5                                                                              R.sub.10                                                                             B                                    ______________________________________                                        23    triethyl    CH.sub.3 CH.sub.3                                                                             CH.sub.3                                                                             C═O                                    orthoacetate                                                            24    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                   orthopropionate                                                         25    triethyl    CH.sub.3 CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2                                   orthoacetate                                                            26    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.3                                                                             CH.sub.3                                                                             C═O                                    orthopropionate                                                         27    triethyl    CH.sub.3 CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             CH.sub.2                                   orthoacetate                                                            28    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             CH.sub.2                                   orthopropionate                                                         29    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             C═O                                    orthopropionate                                                         30    triethyl    CH.sub.3 CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    CH.sub.2                                   orthoacetate                                                            31    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    CH.sub.2                                   orthopropionate                                                         32    triethyl    CH.sub.3 CH.sub.2 CH.sub.3                                                                    CH.sub.3                                                                             C═O                                    orthoacetate                                                            33    triethyl    CH.sub.3 CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    C═O                                    orthoacetate                                                            34    triethyl    CH.sub. 3                                                                              CH.sub.3                                                                             CH.sub.2 Ph                                                                          CH.sub.2                                   orthoacetate                                                            35    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.3                                                                             CH.sub.2 Ph                                                                          CH.sub.2                                   orthopropionate                                                         36    triethyl    CH.sub.3 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    CH.sub.2                                   orthoacetate                                                            37    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    CH.sub.2                                   orthopropionate                                                         38    triethyl    CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.3                                                                    C═O                                    orthopropionate                                                         39    triethyl    H        CH.sub.3                                                                             CH.sub.3                                                                             C═O                                    orthoformate                                                            40    triethyl    H        CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    CH.sub.2                                   orthoformate                                                            ______________________________________                                    

EXAMPLE 41 Step 2

Preparation of8,9-Dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b]-[[1,4]oxazin-8-one

One gram (4.05 mmole) of crude8,9-dihydro-5,7-dimethyl-3-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4]-oxazin-8-oneobtained in Step 1, Example 1 was dissolved in 20 ml of methanol. Twodrops of 25% sodium methoxide solution were added and the solution washeated at its reflux temperature for one hour. The solution wasevaporated under vacuum and the residue was dissolved in dichloromethaneand eluted through a flash chromatography column with 1:1 (by volume)dichloromethane:ethyl acetate to obtain a white solid which wasrecrystallized from a benzene-hexane mixture to provide8,9-dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazin-8-one,m.p. 169-170° C. Analysis: Calculated for C₁₁ H₁₃ N₅ O₂ : %C, 54.4; %H,5.3; %N, 28.3; Found: %C, 53.4; %H, 5.2; %N, 28.5.

EXAMPLES 42-62

Using the method of Step 2, Example 41, the indicated intermediate ofFormula V wherein Y is O, Q is N-R₇ and B is methylene or -CHR₉ - wasreacted with methanolic sodium methoxide to provide the indicatedproduct of Formula VI (TABLE IIA).

                                      TABLE IIA                                   __________________________________________________________________________    Intermediate                          Calculated:                                                                         % C;                                                                             % H;                                                                              % N                        from        Product of Formula VI     Found:                                                                              % C;                                                                             % H;                                                                              % N                        Example                                                                            Example                                                                              R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                            B      A         (m.p. in °C.)              __________________________________________________________________________    42    2     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CH.sub.2                                                                             C═O   51.5;                                                                            4.75;                                                                             30.0                                                                   51.5;                                                                            4.7;                                                                              30.0                                                                   (284-285)                         43    3     H    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             C═O   53.4;                                                                            5.3;                                                                              28.3                                                                   53.8;                                                                            5.5;                                                                              28.3                                                                   (113-114)                         44    4     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             C═O   54.9;                                                                            6.4;                                                                              24.6                                                                   [· 1/2 H.sub.2 O];                                                   55.4;                                                                            6.1;                                                                              24.5                                                                   (78-80)                           45    5     H    CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2                                                                             C═O   49.3;                                                                            4.1;                                                                              31.95                                                                  49.3;                                                                            4.2;                                                                              31.8                                                                   (210-211)                         46    6     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   55.3;                                                                            5.8;                                                                              26.9                                                                   (153-154)                         47    7     CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2                                                                             C═O   51.5;                                                                            4.75;                                                                             30.0                                                                   51.5;                                                                            4.7;                                                                              30.1                                                                   (195-196)                         48    8     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2                                                                             C═O   53.4;                                                                            5.3;                                                                              28.3                                                                   53.3;                                                                            5.3;                                                                              28.4                                                                   (201-202)                         49    9     H    CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2                                                                             C═O   51.5;                                                                            4.75;                                                                             30.0                                                                   51.7;                                                                            4.8;                                                                              29.9                                                                   (174-175)                         50   10     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H    CH.sub.2                                                                             C═O   53.4;                                                                            5.3;                                                                              28.3                                                                   53.2;                                                                            5.4;                                                                              28.0                                                                   (231-233)                         51   11     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CHCH.sub.2 CH.sub.3                                                                  C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   54.9;                                                                            5.6;                                                                              26.7                                                                   (185-186)                         52   12     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CHCH.sub.3                                                                           C═O   53.4;                                                                            5.3;                                                                              28.3                                                                   53.4;                                                                            5.4;                                                                              28.7                                                                   (145-146)                         53   13     CH.sub.3                                                                           CH.sub.3                                                                           H    CHCH.sub.3                                                                           C═O   51.5;                                                                            4.75;                                                                             30.0                                                                   51.0;                                                                            4.8;                                                                              30.2                                                                   (149-151)                         54   14     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H    CHCH.sub.2 CH.sub.3                                                                  C═O   56.7;                                                                            6.2;                                                                              25.4                                                                   56.4;                                                                            6.3;                                                                              25.7                                                                   (217-218)                         55   15     CH.sub.3                                                                           CH.sub.2 CH.sub. 3                                                                 H    CHCH.sub.2 CH.sub.3                                                                  C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   54.7;                                                                            5.8;                                                                              26.4                                                                   (208-209)                         56   16     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H    CHCH.sub.3                                                                           C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   54.6;                                                                            5.8;                                                                              26.8                                                                   (229-230)                         57   17     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2                                                                             C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   55.3;                                                                            5.8;                                                                              26.9                                                                   (138-139)                         58   18     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H    CH.sub.2                                                                             CH.sub.2  54.8;                                                                            6.0;                                                                              31.9                                                                   54.9;                                                                            6.0;                                                                              31.7                                                                   (173-175)                         59   19     H    CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             CH.sub.2  54.8;                                                                            6.0;                                                                              31.9                                                                   54.8;                                                                            6.1;                                                                              31.9                                                                   (133-134)                         60   20     CH.sub.3                                                                           CH.sub. 3                                                                          CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             CH.sub.2  56.6;                                                                            6.5;                                                                              30.0                                                                   57.0;                                                                            6.6;                                                                              30.3                                                                   (137-138)                         61   21     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2                                                                             CH.sub.2  58.3;                                                                            6.9;                                                                              28.3                                                                   58.3;                                                                            6.9;                                                                              28.6                                                                   (119-120)                         62   22     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2                                                                             CH.sub.2  56.6;                                                                            6.5;                                                                              30.0                                                                   56.4;                                                                            6.5;                                                                              30.0                                                                   (135-136)                         __________________________________________________________________________

EXAMPLES 63-14 78

Using the method of Step 2, Example 41, the indicated intermediate ofFormula V wherein Y is N-R₁₀, Q is O and A is methylene was reacted withmethanoloc sodium methoxide to provide the indicated product of FormulaVI (TABLE IIB).

                                      TABLE IIB                                   __________________________________________________________________________    Intermediate                   Calculated:                                                                         % C;                                                                             % H;                                                                              % N                               from        Product of Formula VI                                                                            Found:                                                                              % C;                                                                             % H;                                                                              % N                               Example                                                                            Example                                                                              R.sub.2                                                                            R.sub.5                                                                            R.sub.10                                                                           B   (m.p. in °C.)                           __________________________________________________________________________    63   23     CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           C═O   51.5;                                                                            4.75;                                                                             30.0                                                                   51.7;                                                                            4.8;                                                                              29.8                                                                   (193-194)                                64   24     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2  56.6;                                                                            6.5;                                                                              30.0                                                                   56.7;                                                                            6.5;                                                                              30.2                                                                   (97-98)                                  65   25     CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2  54.8;                                                                            6.0;                                                                              31.9                                                                   54.5;                                                                            6.0;                                                                              31.8                                                                   (140-141)                                66   27     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2  56.6;                                                                            6.5;                                                                              30.0                                                                   56.5;                                                                            6.4;                                                                              30.0                                                                   (123-124.5)                              67   28     CH.sub.2 CH.sub.3                                                                  CH.sub. 2 CH.sub.3                                                                 CH.sub.3                                                                           CH.sub.2  58.3;                                                                            6.9;                                                                              28.3                                                                   58.0;                                                                            6.9;                                                                              28.5                                                                   (67-70)                                  68   29     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   55.3;                                                                            5.8;                                                                              27.0                                                                   (99-100.5)                               69   30     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2  58.3;                                                                            6.9;                                                                              28.3                                                                   58.6;                                                                            7.0;                                                                              28.6                                                                   (81-82)                                  70   31     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2  59.7;                                                                            7.3;                                                                              26.8                                                                   59.2;                                                                            7.3;                                                                              26.7                                                                   (60-62.5)                                71   32     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           C═O   53.4;                                                                            5.3;                                                                              28.3                                                                   53.5;                                                                            5.3;                                                                              28.2                                                                   (133-134)                                72   35     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2 Ph                                                                        CH.sub.2  66.0;                                                                            6.2;                                                                              22.6                                                                   65.8;                                                                            6.2;                                                                              22.1                                                                   (89-90)                                  73   36     CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2  56.6;                                                                            6.5;                                                                              30.0                                                                   56.6;                                                                            6.6;                                                                              30.3                                                                   (111-113)                                74   34     CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.2 Ph                                                                        CH.sub.2  65.1;                                                                            5.8;                                                                              23.7                                                                   64.7;                                                                            5.8;                                                                              23.6                                                                   (92-95)                                  75   37     CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2  58.3;                                                                            6.9;                                                                              28.3                                                                   58.5;                                                                            7.0;                                                                              28.6                                                                   (83-84)                                  76   33     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  C═O   55.2;                                                                            5.8;                                                                              26.8                                                                   55.2;                                                                            5.8;                                                                              26.9                                                                   (120-121)                                77   38     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  C═O   56.7;                                                                            6.2;                                                                              25.4                                                                   56.8;                                                                            6.2;                                                                              25.5                                                                   (73.5-76)                                78   40     H    CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2  54.8;                                                                            6.0;                                                                              31.9                                                                   55.0;                                                                            6.0;                                                                              32.3                                                                   (85-88)                                  __________________________________________________________________________

EXAMPLE 79 Preparation of8,9-Dihydro-2,5-dimethyl-7-ethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]oxazine dihydrogen sulfate

One gram (4.3 mmole) of 8,9-dihydro-2,5-dimethyl-7-ethyl-1,2,4-triazolo1,5-c]pyrimido[5,4-b][1,4]oxazine, obtained in Example 42, was dissolvedin 5 ml of ethanol. Concentrated sulfuric acid (0.42g, 4.3 mmole) wasadded, followed by the addition of diethyl ether to precipitate a whitesolid which was filtered, washed with diethyl ether and then dried toprovide 8,9-dihydro-2,5-dimethyl-7-ethyl1,2,4-triazolo[1,5-c]pyrimido5,4-b][1,4]oxazine dihydrogen sulfate, m.p. 245-246° C. Analysis:Calculated for C₁₁ H₁₅ N₅ O·H₂ SO₄ : %C, 39.9; %H, 5.2; %N, 21.1; Found:%C, 40.3; %H, 5.4; %N, 20.7.

EXAMPLE 80 STEP 3

Preparation of 4-chloro-6,7-dihydro-2,8-dimethyl-pyrimido-85,4-b]1,4]oxazin-7-one

Using the method of Sazonov, et al., Khimiya GeterotsiklicheskikhSoedinenii, 9, 1285-1288 (1972),4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4b][1,4]oxazin-7-one one wasprepared. To a mixture of 8.0g (0.0402 mole) of4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one and17.9 ml of methyl iodide was added 8.75g of 25% sodium methoxide in 250ml of methanol, and the solution was heated at its reflux temperaturefor three hours. The solvent was removed by evaporation under vacuum,and the solid was separated by filtration, washed with water, and dried.The yellow solid was4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4b][1,4]oxazin-7-one, m.p.142-143° C.

EXAMPLE 81

To a stirred suspension of 5g (0.023 mole) of4-chloro-6,7-dihydro-2-ethyl-5H-pyrimido[4,5-b][1,4]oxazin-6-one(prepared using the method of Melik-Ogandzhanyan, et al., KhimiyaGeterotsiklicheskikh Soedinenii, 1985, 974) in 100 ml ofN,N-dimethylformamide was added 0.75g (0.025 mole) of 80% sodium hydridein oil. After ten minutes 3.5g (0.025 mole) of methyl iodide was added.After two hours the solution was diluted with about 400ml of water, andextracted thrice with 250ml portions of chloroform. The extracts werewashed with water, dried over magnesium sulfate, treated withdecolorizing charcoal, and evaporated in vacuo. The resulting oil wastriturated with a mixture of diethyl ether and hexanes to provide lightgreen solid4-chloro-6,7-dihydro-2-ethyl-5-methylpyrimido[4,5-b][1,4]oxazin-6-one.

EXAMPLES 82-84

Using the method described in Example 81 the following compounds ofFormula VIII wherein Q is O, A is methylene and B is carbonyl wereprepared.

    ______________________________________                                                    Product of Formula VIII                                           Example       R.sub.5      R.sub.10                                           ______________________________________                                        82            CH.sub.3     CH.sub.2 CH.sub.3                                  83            CH.sub.2 CH.sub.3                                                                          CH.sub.2 CH.sub.3                                  84            CH.sub.3     CH.sub.3                                           ______________________________________                                    

EXAMPLE 85

Using the procedure of Example 80,4-chloro-6,7-dihydro-2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one wasalkylated providing 4-chloro-6,7-dihydro-2-ethyl-8-methylpyrianido5,4-b][1,4]oxazin-7-one.

EXAMPLE 86

Using the procedure of Example 80, except that 1-bromoethane was usedinstead of methyl iodide,4-chloro-6,7-dihydro-2-ethyl-8H-pyrimido[5,4-b][1,4]oxazin-7-one wasalkylated providing 4-chloro-2,8-diethyl-6,7dihydropyrimido[5,4-b][1,4]oxazin-7-one.

EXAMPLE 87 Step 4 Preparation of 6,7-Dihydro-2,8-dimethyl-4-hydrazinopyrimido[5,4-b][1,4]oxazin-7-one

To a solution of 5.78g (0.0271 mole) of4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4-b][1,4]- oxazin-7-one,obtained from Example 80, in 100 ml of n-butyl alcohol was added 1.74g(0.0543 mole) of hydrazine hydrate, and the mixture was heated at itsreflux temperature for three hours. On cooling a solid precipitated andwas separated by filtration, washed with water and dried. The structureof the light yellow product was6,7-dihydro-2,8-dimethyl-4-hydrazinopyrimido[5,4b][1,4]oxazin-7-oneaccording to infrared spectral analysis.

EXAMPLES 88-89

Using the procedure of Example 87, the intermediates of Example 85 andExample 86 were independently reacted with hydrazine hydrate to providethe novel compounds6,7-dihydro-2-ethyl-4-hydrazino-8methylpyrimido[5,4-b][1,4]oxazin-7-oneand 2,8-diethyl-6,7- dihydro-4-hydrazinopyrimido[5,4-b][1,4]oxazin-7-onerespectively.

EXAMPLE 90-98

The method of Sazonov, et al., Khimiya Geterotsiklicheskikh Soedinenii,9, 1285-1288 (1972), was used to prepare the4-chloropyrimido[5,4-b][1,4]oxazin-7-ones which were independentlyreacted with hydrazine hydrate, according to the procedure of Example87, to provide the novel compounds of Formula IV (TABLE IIIA).

                  TABLE IIIA                                                      ______________________________________                                                 Compound of Formula IV                                               Example    R.sub.5    R.sub.7    B                                            ______________________________________                                        90         CH.sub.3   CH.sub.3   CH.sub.2                                     91         CH.sub.3   H          CH.sub.2                                     92         CH.sub.2 CH.sub.3                                                                        CH.sub.2 CH.sub.3                                                                        CH.sub.2                                     93         CH.sub.2 CH.sub.3                                                                        CH.sub.3   CH.sub.2                                     94         CH.sub.2 CH.sub.3                                                                        H          CH.sub.2                                     95         CH.sub.3   H          CHCH.sub.2 CH.sub.3                          96         CH.sub.3   H          CHCH.sub.3                                   97         CH.sub.2 CH.sub.3                                                                        H          CHCH.sub.2 CH.sub.3                          98         CH.sub.2 CH.sub.3                                                                        H          CHCH.sub.3                                   ______________________________________                                    

EXAMPLES 99-101

The method of step 4, Example 87 was used to prepare the novel compoundsof Formula IV wherein Q is O, Y is N-R₁₀ and A is methylene as shown inTable IIIB.

                  TABLE IIIB                                                      ______________________________________                                               Intermediate                                                                              Compound of Formula IV                                     Example  from Example  R.sub.5    R.sub.7                                     ______________________________________                                         99      84            CH.sub.3   CH.sub.3                                    100      83            CH.sub.2 CH.sub.3                                                                        CH.sub.2 CH.sub.3                           101      81            CH.sub.2 CH.sub.3                                                                        CH.sub.3                                    ______________________________________                                    

EXAMPLE 102 Step 5

Preparation of 4-Chloro-6,7-dihydro-8-ethyl-2-methylpyrimido[5,4-b][1,4]oxazine

A solution of 2.0g (8.81 mmole) of4-chloro-6,7-hydro8-ethyl-2-methylprimido[5,4-b][1,4oxazin -7-one in 25ml of tetrahydrofuran was added dropwise to 3.5 ml of cold (0° C.)borane-methyl sulfide complex in tetrahydrofuran. After the completionof the addition, the mixture was heated at its reflux temperature forthree hours. The mixture was cooled and 14 ml of 6N hydrochloric acidwas slowly added. This mixture was heated for one hour at 115° C., andwas then cooled and neutralized with ammonium hydroxide. The mixture wasextracted with chloroform, and the organic layer was then dried andevaporated to provide an oil residue which crystallized on cooling.Nuclear magnetic resonance spectral analysis showed the product to be4-chloro-6,7-dihydro-8-ethyl-2methylpyrimido[5,4-b][1,4]oxazine.

EXAMPLES 103-104

Using the method of Example 102,4-chloro-6,7-dihydro-2,8-dimethylpyrimido 5,4-b][1,4]oxazin-7-one and4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4b][1,4]oxazin-7-one werereduced to white solids4-chloro-6,7-dihydro-2,8-dimethylpyrimido[5,4-b][5,4-b][1,4]oxazine and4-chloro-6,7-dihydro-2-methyl-8H-pyrimido[5,4b][1,4]oxazine,respectively.

EXAMPLE 105 2-methylpyrimido[5,4-b][1,4]oxazine

Using the method of Example 87,4-chloro-6,7-dihydro-8-ethyl-2-methylpyrimido [5,4-b][1,4]oxazine, fromExample 102, was reacted with hydrazine hydrate to provide6,7-dihydro-8-ethyl-4-hydrazino-2-methylpyrimido[5,4-b][1,4]oxazine.

EXAMPLES 106-107

Using the procedure of Example 105, the indicated intermediates ofFormula X were reacted with hydrazine hydrate to provide the compoundsof Formula IV wherein Y is O, Q is N-R₇, and A and B are methylene(TABLE IV).

                  TABLE IV                                                        ______________________________________                                               Intermediate                                                                             Intermediate of Formula X                                          from       and Compound of Formula IV                                  Example  Example      R.sub.5    R.sub.7                                      ______________________________________                                        106      103          CH.sub.3   CH.sub.3                                     107      104          CH.sub.3   H                                            ______________________________________                                    

EXAMPLE 108 Step 9

Preparation of5-Ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione

The general procedure of Gewald, J. Prakt, Chem., 32,26-30 (1966) wasused to prepare 4-amino-3-methylthiazoline-2-thione-5-carboxamide, ofwhich 27.3g (0.14 mole) was suspended in a mixture of approximately144ml of acetic anhydride and about 144ml of triethyl orthopropionate.The resultant mixture was refluxed for approximately one half hour, thencooled in an ice bath. The solid which precipitated was separated byfiltration, washed with diethyl ether and dried in a vacuum oven atapproximately 100° C. to provide 21.4g (65%) of5-ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. Infraredspectral analysis confirmed the structural assignment.

EXAMPLES 109 AND 110

Utilizing the procedure of Example 108, the designated intermediates ofFormula XI were reacted with triethyl orthopropionate to provide thecorresponding compounds of Formula XIII listed in TABLE V, thestructures of which were confirmed by the indicated spectral analysis.

                  TABLE V                                                         ______________________________________                                               Intermediate                                                                  of Formula XI                                                                 and Compounds                                                                 of Formula XIII                                                                            Reflux Time                                                                              Yield Spectral                                 Example                                                                              R.sub.7      (in min.)  (%)   Analysis                                 ______________________________________                                        109    (CH.sub.2).sub.3 CH.sub.3                                                                  30         59    IR, NMR                                  110    CH.sub.2 Ph  30-60      53    IR, NMR                                  ______________________________________                                    

EXAMPLE 111 Step 9

Preparation of 3,5-Dimethyl-6H-thiazolo[4,5d]pyrimidin-7-one-2-thione

Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4g, 6.4mmoles), prepared according to the procedure of Gewald, J. Prakt. Chem.,32, 26-30 (1966), was suspended in approximately 40ml of ethanol.Acetamidine hydrochloride (0.6g, 6.4 mmole) and 2.77g (12.8 mmole) of a25% solution of sodium methoxide in methanol were added to thesuspension and the resultant mixture refluxed for approximately 20hours. The ethanol was removed in vacuo and the residue was suspended inwater and neutralized with concentrated hydrochloric acid. The resultantprecipitate was filtered and dried to provide 1g of3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structuralassignment was confirmed by nuclear magnetic resonance spectralanalysis.

EXAMPLE 112 Step 10

Preparation of 2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one

5-Ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione (9.5g, 41.8mmole) from Example 108 was suspended in approximately 500ml of 4Nsodium hydroxide solution. The resultant mixture was refluxed for 2 to 4hours, followed by cooling at approximately 4° C. for about hours. Themixture was slowly acidified with concentrated hydrochloric acid; thesolid was separated by filtration and dried, providing 6.6g (85%) of2-ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one. Infrared andnuclear magnetic resonance spectral analyses confirmed the structuralassignment.

EXAMPLES 113 AND 114

Using the procedure of Example 112, the intermediates of Formula XIIIwere refluxed in sodium hydroxide solution, then acidified to providethe compounds of Formula XIV listed in TABLE VI, the structures of whichwere confirmed by the indicated spectral analysis.

                  TABLE VI                                                        ______________________________________                                                         Intermediate                                                         Inter-   of Formula XIII                                                      mediate  and Compound                                                         from     of Formula XIV                                                                             Yield  Spectral                                 Example Example  R.sub.7      (%)    Analysis                                 ______________________________________                                        113     109      (CH.sub.2).sub.3 CH.sub.3                                                                  98     IR, NMR                                  114     110      CH.sub.2 Ph  96     IR, NMR                                  ______________________________________                                    

EXAMPLE 115 Step 11

Preparation of6,7-Dihydro-2-ethyl-8-methyl-3H-pyrimido[5,4-b][1,4]thiazine-4,7-dione

2-Ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one (6.6g, 0.036 mole)from Example 112 and 3.37g (0.036 mole) of chloroacetic acid were addedto approximately 120ml of water containing 4.27g (0.107 mole) of sodiumhydroxide. The resultant solution was refluxed for approximately 4hours, allowed to cool and acidified to about pH 2 with concentratedhydrochloric acid. The white solid was separated by filtration and dried(7.4g), then refluxed in approximately 100ml of acetic anhydride forabout 2 hours and allowed to cool. The precipitate was removed bysuction filtration, washed with diethyl ether and dried, providing 6.26g(78%) of6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido[5,4-b][1,4]thiazane-4,7-dione.The structural assignment was confirmed by infrared spectral analysis.

EXAMPLES 116 AND 117

Utilizing the method of Example 115, the intermediates of Formula XIVwere converted to the compounds of Formula XV listed in TABLE VII, thestructures of which were confirmed by the indicated spectral analysis.

                  TABLE VII                                                       ______________________________________                                                          Intermediate                                                                  of Formula XIV                                                     Intermediate                                                                             and Compound                                                       from       of Formula XV                                                                              Yield Spectral                                 Example                                                                              Example    R.sub.7      (%)   Analysis                                 ______________________________________                                        116    113        (CH.sub.2).sub.3 CH.sub.3                                                                  36    IR, NMR                                  117    114        CH.sub.2 Ph  41    IR, NMR                                  ______________________________________                                    

EXAMPLE 118

2Ethyl-5-mercapto-6-benzylamino-3H-pyrimidin-4-one (10.0g, 0.038 mole)from Example 114 was suspended in approximately 100ml of watercontaining 4.6g (0.115 mole) of sodium hydroxide and the suspension wasstirred for about 10 minutes. 2-Bromobutyric acid (6.39g, 0.038 mole)was added and the resultant mixture refluxed for about 2 hours, allowedto cool and acidified to approximately pH 4-5 with concentratedhydrochloric acid. The precipitate was separated by filtration and driedproviding 8.8g which was suspended in approximately 100ml of aceticanhydride, refluxed for about one hour and then allowed to cool. Sinceno solid precipitated on cooling, a stream of nitrogen was blown overthe solution to evaporate the acetic anhydride. The residue was thendissolved in methylene chloride and flash chromatographed, eluting with1:10 (by volume) ethyl acetate:methylene chloride. Evaporation provided3.0g (24%) of yellow solid,2,6-diethyl-6,7-dihydro-8-benzyl-3H-pyrimido[5,4-b][1,4]thiazine-4,7-dione.Infrared spectral analysis confirmed the structural assignment.

EXAMPLE 119 Step 12

Preparation of4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido[5,4-b][1,4]thiazin-7-one

The6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido-[5,4-b][1,4]thiazine-4,7-dioneof Example 115 (2.7g, 12.04 mmole) was suspended in approximately 150mlof phosphorus oxychloride and refluxed for about 20 hours. The solutionwas concentrated in vacuo and the excess phosphorus oxychloride wasdecomposed with the careful addition of ice and water. The aqueoussolution was neutralized with the cautious addition of concentratedammonium hydroxide, followed by the addition of sodium bicarbonate. Theaqueous solution was extracted numerous times with chloroform; theextracts were combined, washed well with water, then brine, dried overmagnesium sulfate, filtered and evaporated in vacuo to provide 2.4g(83%) of an off-white solid. The structural assignment was confirmed byinfrared and nuclear magnetic resonance spectral analyses.

EXAMPLES 120-122

Utilizing the method of Example 119, the intermediates of Formula XVwere chlorinated, providing the compounds of Formula XVI listed in TABLEVIII. These compounds were isolated as oils and required furtherpurification utilizing flash chromatography, eluting with methylenechloride. The structural assignment of the compounds was confirmed bynuclear magnetic resonance spectral analysis.

                                      TABLE VIII                                  __________________________________________________________________________    Inter-                                                                        mediate   Intermediate of Formula XV                                          from      and Compound of Formula XVI                                                                     Yield                                                                             Spectral                                      Example                                                                            Example                                                                            R.sub.5                                                                            R.sub.7                                                                             B      (%) Analysis                                      __________________________________________________________________________    120  116  CH.sub.2 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                                                           CH.sub.2                                                                             74  NMR                                           121  117  CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                         CH.sub.2                                                                             43  NMR                                           122  118  CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                         CHCH.sub.2 CH.sub.3                                                                  60  NMR                                           __________________________________________________________________________

EXAMPLE 123 Step 13

Preparation of 6,7-Dihydro-2-ethyl-4-hydrazino-8methylpyrimido[5,4-b][1,4]thiazin-7-one

4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido[5,4-b][1,4]thiazin-7-onefrom Example 119 (2.4g, 9.93 mmole) was suspended in approximately 100mlof n-butanol. Hydrazine monohydrate (0.99g, 19.9 mmole) was added andthe resultant mixture was refluxed for about 20 hours. The reactionmixture was allowed to cool and the precipitate was separated byfiltration, washed with water and dried, providing 1.93g (81%) of6,7-dihydro-2-ethyl-4-hydrazino-8-methylpyrimido[5,4-b][1,4]thiazin-7-one. Infrared and nuclear magnetic resonancespectral analyses confirmed the structural assignment.

EXAMPLES 124-125

Using the procedure of Example 123, the intermediates of Formula XVIwere reacted with hydrazine monohydrate to provide the respectiveintermediates of Formula XVII listed in TABLE IX. For Example 125, thereaction mixture was refluxed for about 3 hours instead of approximately20 hours. The structures were confirmed by the indicated spectralanalysis.

                                      TABLE IX                                    __________________________________________________________________________    Inter-                                                                        mediate   Intermediate of Formula XVI                                         from      and Compound of Formula XVII                                                                    Yield                                                                             Spectral                                      Example                                                                            Example                                                                            R.sub.5                                                                            R.sub.7                                                                             B      (%) Analysis                                      __________________________________________________________________________    124  120  CH.sub.2 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                                                           CH.sub.2                                                                             93  IR, NMR                                       125  122  CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                         CHCH.sub.2 CH.sub.3                                                                  85  NMR                                           __________________________________________________________________________

EXAMPLE 126 Step 14

Preparation of8,9-Dihydro-3,7-dimethyl-5-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4thiazin-8-one

Approximately 20ml of triethyl orthoacetate was added to 1.lg (4.6mmole) of6,7-dihydro-2-ethyl-4-hydrazino-8-methylpryimido[5,4-b][1,4thiazin-7-onefrom Example 123) and the mixture heated at approximately 115° C. forabout 20 hours. The reaction mixture was cooled in an ice bath; theprecipitate was separated by filtration, washed with diethyl ether anddried, providing 0.65g (54%) of8,9-dihydro-3,7-dimethyl-5-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4]thiazin-8-one.Nuclear magnetic resonance spectral analysis confirmed the structuralassignment.

EXAMPLES 127-130

Using the procedure of Example 126, the intermediates of Formula XVIIwere reacted with the indicated orthoester to provide the intermediatesof Formula XVIII listed in TABLE X. The solid residues of Examples 128,129 and 130 were triturated with hexanes, then separated by filtration,washed with diethyl ether and dried. The structural assignment of thecompounds was confirmed by nuclear magnetic resonance spectral analysis.

                                      TABLE X                                     __________________________________________________________________________    Intermediate                                                                  from                Compound of Formula XVIII                                                                            Yield                              Example                                                                            Example                                                                              Orthoester                                                                            R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                             B      (%)                                __________________________________________________________________________    127  123    triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                            CH.sub.2                                                                             63                                             orthopropionate                                                   128  124    triethyl                                                                              CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                                                           CH.sub.2                                                                             89                                             orthoacetate                                                      129  124    triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                                                           CH.sub.2                                                                             67                                             orthopropionate                                                   130  125    triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                         CHCH.sub.2 CH.sub.3                                                                  56                                             orthopropionate                                                   __________________________________________________________________________

EXAMPLE 131 Step 15

Preparation of 8,9-Dihydro-2,7-dimethyl-5-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazin-8-one

To approximately 20ml of methanol to which had been added 3-5 drops of a25% solution of sodium methoxide in methanol was added 0.65g (2.5 mmole)of 8,9-dihydro- 3,7 -dimethyl-5-ethyl-1,2,4-triazolo[4,3-c]pyrimido[5,4-b][1,4]thiazin-8-one (from Example 126). Thereaction mixture was refluxed for about 20 hours and allowed to cool.The precipitate was separated by filtration, washed with water anddried, providing 0.48g (74%) of8,9-dihydro-2,7-dimethyl-5-ethyl-1,2,4-triazolo1,5-c]pyrimido[5,4-b]-[1,4]thiazin-8-one, m.p. 187-188° C. Analysis:Calculated for C₁₁ H₁₃ N₅ OS: %C, 50.2; %H, 5.0; %N, 26.6; Found: %C,50.1; %H, 4.9; %N, 26.7. The structural assignment was confirmed byinfrared and nuclear magnetic resonance spectral analyses.

EXAMPLES 132-135

Using the procedure of Example 131, the intermediates of Formula XVIIIwere rearranged to provide the compounds of Formula XIX, a subset ofcompounds of Formula I, listed in TABLE XI. For Examples 133 and 134,the reaction solution was concentrated in vacuo, and the resulting solidwas purified by flash chromatography, eluting with 1:9 (by volume) ethylacetate:methylene chloride. For Example 135, after reflux for about 2hours, the reaction solution was concentrated in vacuo and then purifiedby flash chromatography, eluting with methylene chloride. The structuralassignment of the compounds was confirmed by infrared and nuclearmagnetic resonance spectral analyses.

                                      TABLE XI                                    __________________________________________________________________________    Intermediate                       Calculated:                                                                         % C;                                                                              % H; % N                         from        Product of Formula XIX Found:                                                                              % C;                                                                              % H; % N                         Example                                                                            Example                                                                              R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                             B            (m.p. in °C.)                                                                 [% Yield]                     __________________________________________________________________________    132  127    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                            CH.sub.2     52.0;                                                                             5.5; 25.3                                                                 51.8;                                                                             5.5; 25.5                                                                 (160-161)                                                                              [86]                        133  128    CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                                                           CH.sub.2     55.1;                                                                             6.3; 22.9                                                                 54.9;                                                                             6.3; 22.9                                                                 (144-145)                                                                              [52]                        134  129    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  (CH.sub.2).sub.3 CH.sub.3                                                           CH.sub.2     56.4;                                                                             6.6; 21.9                                                                 56.1;                                                                             6.7; 22.1                                                                 (116-117.5)                                                                            [61]                        135  130    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                         CHCH.sub.2 CH.sub.3                                                                        63.0;                                                                             6.1; 18.4                                                                 62.5;                                                                             6.1; 18.1                                                                 (94-95)  [38]                        __________________________________________________________________________

EXAMPLE 136 Step 16

Preparation of6,7-Dihydro-2-methyl-4(3H)-oxopyrimido[5,4-b][1,4]thiazine5,6-Dihydro-3-ethoxy-2-ethoxycarbonyl-2-H [1,4]thiazine was preparedaccording to the procedure described in Great Britain Patent 2,143,234Aand in Robert N. Henrie II et al, J. Med. Chem., 26, 559-563 (1983).Acetamidine hydrochloride (4.4g, 46.8 mmole) was suspended inapproximately 80ml of ethanol to which was added 20.7g (95.8 mmole) of a25% solution of sodium methoxide in methanol, followed by the additionof 9.4g (43.2 mmole) of5,6-dihydro-3-ethoxy-2-ethoxycarbonyl-2H-[1,4]thiazine. The resultantmixture was refluxed for about 29 hours, allowed to cool andconcentrated in vacuo to provide a brown solid residue. About 40ml ofwater were added to the residue; the suspension was cooled in an icebath and carefully acidified (pH 5-6) with approximately 5ml ofconcentrated hydrochloric acid. The precipitate was separated byfiltration, washed with water and dried in a vacuum oven at about 80° C.for approximately 20 hours, providing 6.7g (85%) of a light tan solid,6,7-dihydro-2-methyl-4(3H)-oxopyrimido[5,4-b][1,4]thiazine. Thestructural assignment was confirmed by nuclear magnetic resonancespectral analysis.

EXAMPLE 137

Following the procedure of Example 136, with the exception thatpropionamidine acetate was used instead of acetamidine hydrochloride,6,7-dihydro-2-ethyl-4(3H)-oxopyrimido[5,4-b][1,4]thiazine was isolatedin 86% yield. The structural assignment was confirmed by nuclearmagnetic resonance spectral analysis.

EXAMPLES 138-139

Step 17

Using the procedure of Step 12, Example 119, the intermediates ofFormula XXI were chlorinated to provide the compounds of Formula XXII aslisted in TABLE XII. For Example 138, filtration following theneutralization of the aqueous solution was necessary to remove a smallamount of particulate matter; the product was isolated as a reasonablypure solid. The structural assignment of the compounds was confirmed bythe indicated spectral analysis.

                                      TABLE XII                                   __________________________________________________________________________    Inter-                                                                        mediate   Intermediate of Formula XXI                                         from      and Compound of Formula XXII                                                                  Yield                                                                              Spectral                                       Example                                                                            Example                                                                            R.sub.5                                                                              R.sub.7                                                                           B    (%)  Analysis                                       __________________________________________________________________________    138  136  CH.sub.3                                                                             H   CH.sub.2                                                                           72   IR, NMR                                        139  137  CH.sub.2 CH.sub.3                                                                    H   CH.sub.2                                                                           92   NMR                                            __________________________________________________________________________

EXAMPLES 140-141

Step 18

Following the procedure of Step 13, Example 123, with the exception thathydrazine hydrate was used neat (about 3 ml/g) instead of hydrazinehydrate in n-butanol, the intermediates of Examples 138 and 139 werereacted to provide the intermediates of Formula XXIII as listed in TABLEXIII. The structures were confirmed by the indicated spectral analysis.

                                      TABLE XIII                                  __________________________________________________________________________    Inter-                                                                        mediate   Intermediate of Formula XXII                                        from      and Compound of Formula XXIII                                                                  Yield                                                                              Spectral                                      Example                                                                            Example                                                                            R.sub.5                                                                              R.sub.7                                                                            B    (%)  Analysis                                      __________________________________________________________________________    140  138  CH.sub.3                                                                             H    CH.sub.2                                                                           87   IR, NMR                                       141  139  CH.sub.2 CH.sub.3                                                                    H    CH.sub.2                                                                           98   NMR                                           __________________________________________________________________________

EXAMPLES 142-144

Step 19

Using the procedure of Step 14, Example 126, the intermediates ofFormula XXIII were reacted with the designated orthoester to provide thecompounds of Formula XXIV as listed in TABLE XIV. For Example 142, thereaction mixture was refluxed for about 3 days instead of approximately20 hours. The structural assignment of the compounds was confirmed bynuclear magnetic resonance spectral analysis.

                                      TABLE XIV                                   __________________________________________________________________________    Intermediate                                                                  from                Compound of Formula XXIV                                                                     Yield                                      Example                                                                            Example                                                                              Orthoester                                                                            R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                         B  (%)                                        __________________________________________________________________________    142  140    triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H CH.sub.2                                                                         96                                                     orthopropionate                                                   143  141    triethyl                                                                              CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  H CH.sub.2                                                                         88                                                     orthoacetate                                                      144  141    triethyl                                                                              CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H CH.sub.2                                                                         90                                                     orthopropionate                                                   __________________________________________________________________________

EXAMPLES 145-147

Step 20

Following the procedure of Step 15, Example 131, the intermediates ofFormula XXIV were rearranged to provide the compounds of Formula XXV aslisted in TABLE XV. For each of the compounds, the reaction mixture wasfor about 5-6 hours, about 4 hours and about 20 hours respectively, thenconcentrated in vacuo. The residue was suspended in water (approximately10ml/g of starting material) and extracted five times with 60ml portionsof chloroform. The combined extracts were washed with about 50ml ofwater, then approximately 75ml of brine, dried over magnesium sulfate,filtered, and concentrated in vacuo to provide a solid which wastriturated with hexanes, filtered and dried, yielding a solid which wasrecrystallized from benzene:hexanes. The structural assignment of thecompounds of Formula XXV, a subset of the compounds of Formula I, wasconfirmed by infrared and nuclear magnetic resonance spectral analyses.

                                      TABLE XV                                    __________________________________________________________________________         Intermediate          Calculated:                                                                         % C;                                                                             % H;                                                                              % N                                        from   Product of Formula XXV                                                                       Found:                                                                              % C;                                                                             % H;                                                                              % N                                   Example                                                                            Example                                                                              R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                         B        (m.p. in °C.)                                                                 [% yield]                             __________________________________________________________________________    145  142    CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           H CH.sub.2 49.2;                                                                            5.8;                                                                              28.7                                                                   48.8;                                                                            5.8;                                                                              29.0                                                                   (139-143)                                                                            [92]                                  146  143    CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  H CH.sub.2 51.0;                                                                            5.6;                                                                              29.8                                                                   50.8;                                                                            5.6;                                                                              29.8                                                                   (139-141)                                                                            [93]                                  147  144    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  H CH.sub.2 53.0;                                                                            6.1;                                                                              28.1                                                                   53.0;                                                                            6.0;                                                                              28.2                                                                   (104-107)                                                                            [62]                                  __________________________________________________________________________

EXAMPLE 148 Preparation of2,5-diethyl-10-oxo-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4-9 thiazine

The sulfoxide of the compound of Example 147 was prepared by dissolving0.5g (2 mmole) of2,5-diethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-]1,4thiazine in a mixtureof approximately 25ml of ethyl alcohol and about 5ml of water. To thissolution was added 1.0g (4.7 mmole) of sodium metaperiodate and theresultant solution was stirred at about 20° C for approximately 2 hours,at which time thin layer chromotographic analysis, eluting with ethylacetate indicated the absence of starting material. The reactionsolution was then diluted with about 150ml of water and extracted thricewith approximately 75ml of chloroform. The chloroform extracts werecombined, dried over magnesium sulfate, filtered and concentrated invacuo to provide a solid in about 87% yield, m.p. 217-219° C. The crudesolid was recrystallized from ethyl acetate to provide 0.25g of2,5-diethyl-10-oxo-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,m.p. 217-219° C. Analysis: Calculated for C₁₁ H₁₅ N₅ SO: %C, 49.8; %H,5,7; %N, 26.4; Found: %C, 49.8; %H, 5.8; %N, 46.9. The structuralassignment was confirmed by infrared and nuclear magnetic resonancespectral analyses.

EXAMPLE 149 Step 21 Preparation of8,9-dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b]1,4]thiazine

The8,9-dihydro-2-ethyl-5-methyl-1,2,4-triazolo-[1,5-c]pyrimido[5,4-b][1,4]thiazineof E 4.3 mmole) was dissolved in approximately 25ml of dryN,N-dimethylformamide and the mixture was stirred under a nitrogenatmosphere at about 20° C. during the addition of 0.2g (5.0 mmole) of a60% oil dispersion of sodium hydride; a yellow solid formed and gasevolution was observed. After addition was complete, the mixture wasallowed to stir for about 20 minutes at which time the solid haddissolved. Methyl iodide (1.2g, 8.5 mmole) was then added with continuedstirring under a nitrogen atmosphere at about 20° C. When addition wascomplete, the solution was allowed to stir at approximately 20° C. forabout 5 hours. The reaction solution was then poured into about 40ml ofwater and extracted five times with 40ml portions of chloroform; thecombined extracts were washed six times with 200ml portions of water,dried over magnesium sulfate, filtered and concentrated in vacuo toprovide a tan oil. The oil was purified by flash chromatography, elutingwith 1:4 (by volume) ethyl acetate:methylene chloride, yielding 0.8g(76%) of a pale yellow solid which on recrystallization from cyclohexaneprovided 0.6g of 8,9-dihydro-5,7-dimethyl-2-ethyl-1,2,4-triazolo1,5-c]pyrimido[5,4-b][1,4]thiazine, m.p. 103-104° C. Analysis Calculatedfor C H >N>S: %C, 53.0; 103-104° H, 6.1; %N, 28.1; Found: %C, 52.6; %H,6.0; %N, 28.4. The structural assignment was confirmed by infrared andnuclear magnetic resonance spectral analyses.

EXAMPLES 150-156

Following the procedure of Example 149, the designated compounds ofFormula XXV were reacted with an alkyl halide to form the compounds ofFormula XXVI, a subset of the compounds of Formula I, as listed in TABLEXVI. For Example 150, after the addition of the alkyl halide, thereaction mixture was refluxed about 2 hours instead of stirring forapproximately 5 hours at about 20° C. For all other examples, thereaction mixture was stirred at approximately 20° C. for about 20 hoursbefore work-up. The structural assignment of the compounds of FormulaXXVI was confirmed by infrared and nuclear magnetic resonance spectralanalyses.

                                      TABLE XVI                                   __________________________________________________________________________         Inter-                                                                        medi-                     Flash Chromato-                                     ate        Product of     graphy Solvent                                                                            Calculated:                                                                         % C;                                                                              % H;                                                                              % N                       from Alkyl Formula XXVI   System [Recrystal-                                                                        Found:                                                                              % C;                                                                              % H;                                                                              % N                  Example                                                                            Example                                                                            Halide                                                                              R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                            lization Solvent]                                                                          (m.p. in °C.)                                                                   [%                       __________________________________________________________________________                                                         yield]                   150  145  CH.sub.3 CH.sub.2 I                                                                 CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  1:4 EtOAc:CH.sub.2 Cl.sub.2                                                                     54.7;                                                                             6.5;                                                                              26.6                                                [Cyclohexane]     54.6;                                                                             6.6;                                                                              26.8                                                                  (91-92) [55]                 151  146  CH.sub.3 I                                                                          CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           1:9 EtOAc:CH.sub.2 Cl.sub.2                                                                     53.0;                                                                             6.1;                                                                              28.1                                                then 1:4 EtOAc:CH.sub.2 Cl.sub.2                                                                52.6;                                                                             6.1;                                                                              28.1                                                                  (159-160)                                                                             [43]                 152  147  CH.sub.3 I                                                                          CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                           (not chromatographed)                                                                           54.7;                                                                             6.5;                                                                              26.6                                                [Petroleum Ether] 55.0;                                                                             6.5;                                                                              26.6                                                                  (75-77) [6]                  153  146  CH.sub.3 CH.sub.2 I                                                                 CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  1:9 EtOAc:CH.sub.2 Cl.sub.2                                                                     54.7;                                                                             6.5;                                                                              26.6                                                [not recrystallized]                                                                            54.7;                                                                             6.5;                                                                              26.6                                                                  (92-93) [21]                 154  147  CH.sub.3 CH.sub.2 I                                                                 CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  1:9 EtOAc:CH.sub.2 Cl.sub.2                                                                     56.3;                                                                             6.9;                                                                              25.2                                                [Petroleum Ether] 56.0;                                                                             6.8;                                                                              25.2                                                                  (75-76) [30]                 155  146  PhCH.sub.2 Cl                                                                       CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                        1:9 EtOAc:CH.sub.2 Cl.sub.2                                                                     62.7;                                                                             5.9;                                                                              21.5                                                [Petroleum Ether] 62.5;                                                                             5.9;                                                                              21.6                                                                  (83-85) [38]                 156  147  PhCH.sub.2 Cl                                                                       CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                  CH.sub.2 Ph                                                                        (not chromatographed)                                                                           63.7;                                                                             6.2;                                                                              20.6                                                [Petroleum Ether] 63.7;                                                                             6.2;                                                                              20.9                                                                  (68-70) [38]                 __________________________________________________________________________

EXAMPLE 157

Preparation of5,7-diethyl-10,10-dioxo-2-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4thiazine

The sulfone of the compound of Example 153 was prepared by dissolving2.0g (7.6 mmole) of5,7-diethyl-2methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine inabout 36ml of chloroform and cooling the resultant solution toapproximately 0° C in an ice bath. To this solution was added, in smallportions, a suspension of 4.0g (18.5 mmole) of meta-chloroperbenzoicacid (80-85% pure) in about 35ml of chloroform. When addition wascomplete, the solution was stirred at about 0° C for approximately 2hours, at which time thin layer chromatographic analysis, eluting withethyl acetate indicated the absence of starting material. The reactionsolution was diluted with about 1 liter of chloroform and washedsequentially with 5% sodium hydroxide solution (thrice with about 500ml)and then with water (thrice with 500ml). The chloroform solution wasdried over magnesium sulfate, filtered and concentrated in vacuo toprovide 2.48g of the light pink solid. The crude solid was purified byflash chromatography, eluting with ethyl acetate. The fractionscontaining the pure compound were combined and concentrated in vacuo.The solid obtained was triturated with hexanes, filtered and dried toprovide 0.5g of5,7-diethyl-10,10-dioxo-2-methyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazineas a white crystalline solid, m.p. 218-221° C. Analysis: Calculated forC₁₂ H₁₇ N₅ SO₂ ; %C, 48.8; %H, 5.8; %N, 23.7; Found: %C, 48 8; %H, 5.8;%N, 23.8. The structural assignment was confirmed by infrared spectralanalysis.

EXAMPLE 158

Preparation of8,9-dihydro-2,5,7-triethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazinedihydrogen sulfate

The dihydrogen sulfate salt of the compound of Example 154 was preparedby dissolving 0.5g (1.8 mmole) of8,9-dihydro-2,5,7-triethyl-1,2,4-triazolo[1,5- C]-dihydro-2,5,7-triethyl[1,5-c]pyrimido[5,4-b][1,4]thiazine in approximately 5ml of ethylalcohol. To this solution, was added dropwise 0.18g (1.8mmole) ofconcentrated sulfuric acid and the resultant solution was diluted withdiethyl ether to produce a slightly cloudy solution. Upon standing atabout 20° C., a solid precipitated. The solid was separated by suctionfiltration and dried in a vacuum oven (without heat) to provide 0.6g(89%) of8,9-dihydro-2,5,7-triethyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazinedihydrogen C₁₃ H₁₉ N₅ S·H₂ SO₄ : %C, 41.6%H, 5.6; %N, 18.7; Found: %C,41.8; %H, 5.7; %N, 18.4.

EXAMPLE 159

Preparation of 7-acetyl-8,9-dihydro-2-ethyl-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine

To a solution of 0.9g (3.62 mmole) of8,9-dihydro-2-ethyl-5-methyl-1,2,4-triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine(from Example 145) in approximately 50ml of chloroform was added 0.4g(4.05 mmole) of triethylamine, followed by the addition of 0.58g (7.4mmole) of acetyl chloride. The reaction mixture was refluxed under anitrogen atmosphere for about 2 hours at which time thin layerchromatographic analysis, eluting with ethyl acetate, indicated that thereaction was complete. After cooling and dilution with about 100ml ofchloroform, the reaction solution was washed twice with 50ml portions ofwater, twice with 40ml portions of a 5% solution of hydrochloric acid,twice with 50ml portions of aqueous sodium bicarbonate solution, twicewith 50ml portions of water, dried over magnesium sulfate, filtered andconcentrated in vacuo to provide a yellow solid. The solid was flashchromatographed, eluting with ethyl acetate, to provide 0.5g (23%) ofproduct which after recrystallization from benzene:hexanes yielded 0.32gof a white solid,7-acetyl-8,9-dihydro-2-ethyl-5-methyl-1,2,4triazolo[1,5-c]pyrimido[5,4-b][1,4]thiazine,m.p. 164-165° C. Analysis: Calculated for C₁₂ :H₁₅ N₅, SO: %C, 52.0; %H,5.5; %N, 25.3; Found: %C, 52.1; %H, 5.5; %N, 25.4. The structuralassignment was confirmed by infrared and nuclear magnetic resonancespectral analyses.

EXAMPLES 160 and 161

Using the procedure of Example 159, the designated compounds of FormulaXXV were reacted with acetyl chloride to provide the compounds ofFormula XXVI, a subset of the compounds of Formula I, as listed in TABLEXVII. For Example 160, after refluxing for about 2 hours, the reactionmixture was stirred at approximately 20° C. for about 20 hours beforework-up.

                                      TABLE XVII                                  __________________________________________________________________________        Intermediate                                                                         Product of                Calculated:                                                                         % C; % H; % N                      Ex- from   Formula XXVI  Flash Chromatography                                                                      Found:                                                                              % C; % H; % N                      ample                                                                             Example                                                                              R.sub.2                                                                            R.sub.5                                                                            R.sub.7                                                                           Elution Solvent System                                                                    (m.p. in °C.)                                                                [% yield]                          __________________________________________________________________________    160 146    CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                   ##STR11##                                                                        1:9 EtOAc:CH.sub.2 Cl.sub.2 then 1:4                                          EtOAc:CH.sub.2 Cl.sub.2 then 1:1 EtOAc:CH.sub.2                               Cl.sub.2          52.0; 5.4; 25.2 52.8; 5.6;                                                    25.2 (189-191) [60]                161 147    CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                   ##STR12##                                                                        1:9 EtOAc:CH.sub.2 Cl.sub.2                                                                     53.06; 5.9; 24.0 53.6  5.8;                                                   24.3 (148-150)                     __________________________________________________________________________                                               [76]                           

EXAMPLES 162-163

Using the method of Example 102 the indicated intermediates were reducedto provide intermediates of Formula X as shown in the following Table.

                  TABLE XVIII                                                     ______________________________________                                                           Compound                                                                      of Formula X                                               Example   Intermediate   R.sub.5  R.sub.10                                    ______________________________________                                        162       Example 81     CH.sub.2 CH.sub.3                                                                      CH.sub.3                                    163       Example 84     CH.sub.3 CH.sub.3                                    ______________________________________                                    

EXAMPLES 164-168

Using the method of Example 87 except no solvent was used, the indicatedintermediates were reacted to provide intermediates of Formula IV asshown in the following Table.

                  TABLE XIX                                                       ______________________________________                                                         Compound                                                                      of Formula IV                                                Example  Intermediate  R.sub.5  R.sub.10                                      ______________________________________                                        164      Example 163   CH.sub.3 CH.sub.3                                      165      Example 162   CH.sub.2 CH.sub.3                                                                      CH.sub.3                                      166      Example 174   CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                             167      Example 173   CH.sub.3 CH.sub.2 Ph                                   168      Example 172   CH.sub.3 CH.sub.2 CH.sub.3                             ______________________________________                                    

EXAMPLES 169-170

Step 7

The method of Melik-Ogandzhanyan, et al., Khimiya GeterotsiklicheskikhSoedinenii, 1985, 974 was used to prepare4-chloro-6,7-dihydro-2-methyl-5H-pyrimido-[4,5-][1,4]oxazin-6-one and4-chloro-6,7-dihydro-2-ethyl-5-H-pyrimido[4,5-][1,4]oxazin-6-one whichwere reacted separately with borane-methyl sulfide complex using themethod of Example 102 to provide intermediates of Formula IX wherein Q₁is O, Q₂ is NH and B is methylene as shown in the following Table.

                  TABLE XX                                                        ______________________________________                                                     Compound                                                                      of Formula IX                                                    Example      R.sub.5                                                          ______________________________________                                        169          CH.sub.3                                                         170          CH.sub.2 CH.sub.3                                                ______________________________________                                    

EXAMPLE 171-174

Step 8

Using the method of Example 81, the indicated intermediates were reactedto provide intermediates of Formula X as shown in the following Table.

                  TABLE XXI                                                       ______________________________________                                                         Compound                                                                      of Formula X                                                 Example  Intermediate  R.sub.5  R.sub.10                                      ______________________________________                                        171      Example 169   CH.sub.3 CH.sub.3                                      172      Example 169   CH.sub.3 CH.sub.2 CH.sub.3                             173      Example 169   CH.sub.3 CH.sub.2 Ph                                   174      Example 170   CH.sub.2 CH.sub.3                                                                      CH.sub.2 CH.sub.3                             ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR13## wherein A ismethylene or carbonyl; B is methylene or --CHR₉ --; Q is N-R₇ ; Y is S,SO or SO₂ ; R₂ is hydrogen or lower alkyl; R₅ is lower alkyl; R₇ ishydrogen, lower alkyl, benzyl or acetyl, with the proviso that when R₇is hydrogen or acetyl, then A is methylene; and R₉ is lower alkyl; or apharmaceutically acceptable acid-addition salt of said compound whereinA is methylene.
 2. A compound according to claim 1, wherein A ismethylene.
 3. A compound according to claim 1, wherein A is carbonyl. 4.A compound of the formula ##STR14## wherein A is methylene or carbonyl;B is methylene or --CHR₉ --; Q is N-R₇ ; Y is S, SO or SO₂ ; R₂ ishydrogen or lower alkyl; R₅ is lower alkyl; R₇ is hydrogen, lower alkyl,benzyl or acetyl, with the proviso that when R₇ is hydrogen or acetyl,then A is methylene; and R₉ is lower alkyl.
 5. A compound according toclaim 4, wherein Y is S, SO, or SO₂.
 6. A compound according to claim 5,wherein A is methylene.
 7. A compound according to claim 5, wherein A iscarbonyl.
 8. A compound according to claim 4, wherein A is methylene. 9.A compound according to claim 4, wherein A is carbonyl.
 10. Abronchodilator pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier, saidcompound being present in an amount sufficient to providebronchodilation.
 11. A method for obtaining bronchodilation is a mammal,comprising administering a bronchodilator compound to said mammal, saidbronchodilator compound being of the formula ##STR15## wherein A ismethylene or carbonyl; B is methylene or --CHR₉ --; Q is N-R₇ ; Y is S,SO or SO₂ ; R₂ is hydrogen or lower alkyl; R₅ is lower alkyl; R₇ ishydrogen, lower alkyl, benzyl or acetyl, with the proviso than when R₇is hydrogen or acetyl, then A is methylene; and R₉ is lower alkyl or apharmaceutically acceptable salt of said compound wherein A ismethylene, said compound being administered to said mammal in an amountsufficient to provide bronchodilation.
 12. A method according to claim11, wherein A is methylene.
 13. A method according to claim 11, whereinA is carbonyl.
 14. A method according to claim 11, wherein said compoundis administered orally.
 15. A compound according to claim 1, selectedfrom the group consistingof2,5-diethyl-8,9-dihydro-7-methyl-1,2,4-triazolo-pyrimidothiazin-8-one,7-2,5-diethyl-8,9-dihydro-1,2,4-triazolo-pyrimidothiazin-8-one,7-benzyl-8,9-dihydro-2,5,9-triethyl-1,2,4-triazolo-pyrimidothiazin-8one,8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolothiazine,7-benzyl-8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolothiazine,5,7-diethyl-8,9-dihydro-2-methyl-1,2,4-triazolo-pyrimidothiazine,7-benzyl-2,5-diethyl-8,9-dihydro-1,2,4-triazolo-pyrimidothiazine,7-8,9-dihydro-5-ethyl-2-methyl-1,2,4-triazolopyrimidothiazin-8-one,2,7-diethyl-8,9-dihydro-5-methyl-1,2,4-triazolo-pyrimidothiazine,2,5-diethyl-8,9-dihydro-1,2,4-triazolothiazine,2,5-diethyl-8,9-dihydro-7-methyl-1,2,4-triazolopyrimidothiazine.